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Epithelial-to-mesenchymal transition (EMT) is a dynamic program of cell plasticity aberrantly reactivated in cancer. The crosstalk between tumor cells and the tumoral microenvironment (TME) has a pivotal importance for the induction of the EMT and the progression toward a malignant phenotype. Notably, exosomes are key mediators of this crosstalk as vehicles of specific molecular signals that include the class of circular RNAs (circRNAs). This review specifically focuses on the role of exosome-associated circRNAs as key regulators of EMT in cancer. The relevance of these molecules in regulating the intercellular communication in TME and tumor progression is highlighted. Moreover, the here-presented evidence indicates that exosome-associated circRNA modulation should be taken in account for cancer diagnostic and therapeutic approaches.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) control gene expression by acting at multiple levels and are often deregulated in epithelial tumors; however, their roles in the fine regulation of cellular reprogramming, specifically in epithelial–mesenchymal transition (EMT), remain largely unknown. Here, we focused on the hnRNP-Q (also known as SYNCRIP), showing by molecular analysis that in hepatocytes it acts as a “mesenchymal” gene, being induced by TGFβ and modulating the EMT. SYNCRIP silencing limits the induction of the mesenchymal program and maintains the epithelial phenotype. Notably, in HCC invasive cells, SYNCRIP knockdown induces a mesenchymal–epithelial transition (MET), negatively regulating their mesenchymal phenotype and significantly impairing their migratory capacity. In exploring possible molecular mechanisms underlying these observations, we identified a set of miRNAs (i.e., miR-181-a1-3p, miR-181-b1-3p, miR-122-5p, miR-200a-5p, and miR-let7g-5p), previously shown to exert pro- or anti-EMT activities, significantly impacted by SYNCRIP interference during EMT/MET dynamics and gathered insights, suggesting the possible involvement of this RNA binding protein in their transcriptional regulation.